A Physical Organic Approach Towards Electrophilic Fluorination

Abstract

Fluorinated compounds have fundamental roles within the pharmaceutical, agrochemical and materials industries. The presence of a fluorine atom can impart beneficial changes to the chemical properties and biological activities of drug molecules, such as improved metabolic stability and enhanced binding interactions. Electrophilic fluorinating reagents of the N−F class, such as Selectfluor™, NFSI and N-fluoropyridinium salts, underpin the introduction of fluorine in aliphatic systems in both academic and industrial research. However, the choice of N−F reagent is currently determined through empirical experimentation in the absence of quantitative values for electrophilicities.
Firstly, this thesis will discuss the development of an experimentally-determined kinetic reactivity scale for ten N−F fluorinating reagents. The reactivity scale, which covers eight orders of magnitude, was determined by measurement of relative and absolute rate constants for the fluorination of a range of para-substituted 1,3-diaryl-1,3-dicarbonyl derivatives. Similar Hammett parameters across the different fluorinating reagents revealed the mechanisms of fluorination to be similar in each case. The 1,3-diaryl-1,3-dicarbonyl compounds delivered a convenient, sensitive spectrophotometric reporter of reactivity that also led to the discovery of a unique form of tautomeric polymorphism.
Given the pharmaceutical relevance of α,α-difluoroketonic compounds, kinetics studies were performed on keto-enol tautomerism and difluorination of 1,3-dicarbonyl systems to understand the factors that determine selectivity between mono- and di-fluorination. Photoketonization of 1,3-diaryl-1,3-dicarbonyl derivatives and their 2-fluoro analogues was coupled with relaxation kinetics to determine enolization rates, where the presence of additives resulted in significant acceleration of enolization processes in 2-fluoro-1,3-dicarbonyl systems.
Kinetics studies on fluorination were also expanded to other classes of carbon nucleophiles, including indoles and enolates, during attempts to correlate reactivities of the N−F reagents with the Mayr-Patz scale. These experiments provided useful information for determining the reaction monitoring methodology used in other systems and have the potential for further development.
Finally, the studies on fluorination kinetics were expanded to drug-like steroid systems. The kinetics of fluorination of enol ester derivatives of progesterone, testosterone, cholestenone and hydrocortisone by a series of N−F reagents confirmed the applicability of the reactivity scale discussed earlier towards a different class of carbon nucleophiles. Further insight was gained by determination of the epimerisation rates from β- to α-fluoroprogesterone, the more pharmaceutically-relevant isomer.